Effect and regulation of the secondary structure of synthetic poly(α-amino acid) based on ring-opening polymerization

Abstract

Protein is one of the most important components that constitute the organism. A unique property of protein is the adoption of highly ordered secondary structure formed by hydrogen bond. Poly(α-amino acid)s are protein mimics that also present hydrogen bonds in the backbone and similarly adopt secondary structure (e.g., α-helix and β-sheet). In addition, poly(α-amino acid)s usually possess desired biocompatibility and biodegradability. Therefore, they have demonstrated extensive utilities in the biological fields. In this review, we firstly introduced the formation mechanism of ordered secondary structure of poly(α-amino acid)s. In general, α-helix exhibits rigid rod-like structure due to the intramolecular hydrogen bonds, while β-sheet structure is mainly formed based on the intermolecular hydrogen bonds. The polymerization degree of poly(α-amino acid)s that form β-sheet is often lower than that of poly(α-amino acid)s with α-helix structure. Besides, the formation of the random coil structure is often due to the distortion of the backbone. Then, we discussed the impact of side-chain functionalization on the secondary structure and introduced the existing approaches in modulating the secondary structure, such as controlling the electrostatic interaction, polarity, and hydrogen bonds. By maintaining a separation distance of more than 11 σ-bond between the backbone and side charged groups, the poly(α-amino acid) could adopt α-helical structure due to the diminished interference with the backbone hydrogen bonds. The electrostatic interaction among the side chains disturbs the hydrogen bonding, thereby destabilizing the α-helical structure. For instance, the conformation of light-responsive helical poly(α-amino acid)s can transform into random coil due to side-chain electrostatic attraction after irradiation, while random coil-to-helix transition of zwitterionic poly(α-amino acid)s was achieved via elimination of the side-chain electrostatic interaction in response to phosphatase or acidic pH. In addition, the increased polarity of the side chains of polycysteine and poly(homocysteine) derivatives upon oxidation can also realize the order-order and order-disorder transition of the secondary structure. Moreover, the conformation of poly(α-amino acid)s with triazole groups in the side chains can be transformed from random coil to α-helix when the pH value is decreased, mainly due to the change in the side-chain hydrogen bond pattern. We further summarized the impact of secondary structure on the bio-applications of poly(α-amino acid)s, including cell penetration, gene delivery, anti-microbial therapy, self-assembly, and protein modification. Normally, α-helical conformation features strong membrane penetration and thus α-helical poly(α-amino acid)s can mediate effective gene transfection. pH-responsive, coil-helix transitional poly(α-amino acid)s can allow helix formation in the acidic endolysosomes to specifically penetrate endolysosomal membranes, while light-triggered distortion of the helix at the post-transfection state can diminish the long-term materials toxicity. α-Helical poly(α-amino acid)s with well-tailored structure can also enable potent anti-microbial efficiency by disruption bacterial membranes, and conformation transitionable poly(α-amino acid)s can mediate potent yet selective killing of bacteria upon coil-to-helix transition in response to over-produced phosphatases in infected sites or acidic pH in the stomach. In addition, the secondary structure also has a huge impact on the self-assembly behavior of poly(α-amino acid)s or the pharmacological properties of protein drugs modified with poly(α-amino acid)s. Therefore, the research on the secondary structure and function of poly(α-amino acid)s renders great inspiration for its further application.